Preparation of triazoles by organometallic addition to ketones and intermediates therefor

ABSTRACT

The invention provides a process for the preparation of a compound of the formula:  
                 
 
     or an acid addition or base salt thereof,  
     wherein  
     R is phenyl optionally substituted by 1 to 3 substituents each independently selected from halo and trifluoromethyl;  
     R 1  is C 1 -C 6  alkyl; and  
     “Het” is pyrimidinyl optionally substituted by 1 to 3 substituents each independently selected from C 1 -C 4  alkyl, C 1 -C 4  alkoxy, halo, oxo, benzyl and benzyloxy,  
     comprising reaction of a compound of the formula:  
                 
 
     wherein R is as previously defined for a compound of the formula (I), with a compound of the formula:  
                 
 
     wherein R 1  and “Het” are as previously defined for a compound of the formula (I) and X is chloro, bromo or iodo, in the presence of zinc, iodine and/or a Lewis acid and an aprotic organic solvent: said process being optionally followed by conversion of the compound of the formula (I) to an acid addition or base salt thereof.

[0001] This invention relates to a process for the preparation ofalcohols by the addition of organometallic reagents to ketones. Moreparticularly, this invention relates to the reaction of1-phenyl-2-(1H-1,2,4-triazol-1-yl)ethanone derivatives withorganometallic compounds derived from alpha-haloalkylpyrimidines to formtertiary alcohols.

[0002] The reaction of organometallic compounds derived from alkylhalides with aldehydes and ketones to form secondary and tertiaryalcohols, respectively, is well established in the field of organicchemistry. Many different metals and metal derivatives have beenreported as being useful in this type of reaction, including lithium,magnesium, aluminium, tin and zinc, together with salts thereof. Forexample, A. R. Gangloff et al, J. Org. Chem., 57, 4797-4799 (1992)discloses that 2-(bromomethyl)-4-carbethoxy-1,3-oxazole reacts with zincdust to form an organozinc derivative which undergoes nucleophilicaddition to aldehydes and ketones. Also, Chollet et al, Synth. Comm., 19(11 and 12), 2167-2173 (1989) reports the reaction of organozincderivatives of bromoesters with aldehydes and ketones.

[0003] Certain compounds prepared according to the present process aredisclosed in European Patent Application Publication numbers 0357241 and0440372.

[0004] It has now been surprisingly found that certain1-phenyl-2-(1H-1,2,4-triazol-1-yl)ethanone derivatives may be reactedwith organometallic compounds derived from certainalpha-haloalkylpyrimidine derivatives to form tertiary alcohols in goodto excellent yields and with high stereoselectivity using reactionconditions that are particularly suitable for the bulk synthesis of theproduct.

[0005] This finding has been found to be particularly useful for thesynthesis of(2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,a key intermediate for the preparation of(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,a compound having antifungal activity. The syntheses of both of thesecompounds have been described in European Patent Application Publicationnumber 0440372. In this Application,(2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olis prepared by the chromatographic separation of the two pairs ofenantiomers obtained from the addition of an organolithium derivative of4-chloro-6-ethyl-5-fluoropyrimidine to1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone at from −70 to−50° C. The best stereoselectivity that has been obtained in thisaddition is a 1.1:1 molar ratio in favour of the 2R,3S/2S,3Renantiomeric pair with the total isolated yield of all fourstereoisomers being only about 50%, the low yield being thought to bedue to a competing enolisation reaction. These factors, coupled with theneed to operate the addition reaction at very low temperatures and undervery dilute conditions, together with the difficulty in separatingapproximately equimolar amounts of the two pairs of enantiomers at theend of the reaction with the 2R,3R/2S,3S enantiomeric pair beingunwanted, mean that the process is extremely unsuitable for the economicpreparation of the required 2R,3S/2S,3R intermediate on a large scale.

[0006] In contrast, for example, it has now been found that a 9:1 molarratio of the 2R,3S/2S,3R to the 2R,3R/2S,3S enantiomeric pair of3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-oland a 65% isolated total yield of all the enantiomers (as thehydrochloride salts) can be obtained under the reaction conditionsaccording to the present invention that are highly suitable for largescale synthesis of the product.

[0007] However, higher isolated yields have been obtained and highermolar ratios (both in situ and in respect of isolated product) have beendetermined by varying the reaction conditions in accordance with thepresent invention.

[0008] Similar results have been obtained-with a range ofalpha-haloalkyl-pyrimidine substrates.

[0009] Considerable economic advantages result from the yields andstereospecificity achieved.

[0010] The present invention provides a process for the preparation of acompound of the formula:

[0011] or an acid addition or base salt thereof,

[0012] wherein

[0013] R is phenyl optionally substituted by 1 to 3 substituents eachindependently selected from halo and trifluoromethyl;

[0014] R¹ is C₁-C₆ alkyl; and

[0015] “Het” is pyrimidinyl optionally substituted by 1 to 3substituents each independently selected from C₁-C₄ alkyl, C₁-C₄ alkoxy,halo, oxo, benzyl and benzyloxy,

[0016] comprising reaction of a compound of the formula:

[0017] wherein R is as previously defined for a compound of the formula(I), with a compound of the formula:

[0018] wherein R¹ and “Het” are as previously defined for a compound ofthe formula (I) and X is chloro, bromo or iodo, in the presence of zinc,iodine and/or a Lewis acid and an aprotic organic solvent: said processbeing optionally followed by formation of an acid addition or base saltof the product.

[0019] Optionally, lead can also be present in the reaction, either asthe metal per se or in the form of a suitable salt, e.g. a lead (II)halide. It can be added separately or be inherently present in the zincused.

[0020] In the above definitions, alkyl and alkoxy groups containingthree or more carbon atoms may be straight- or branched-chain and “halo”means fluoro, chloro, bromo or iodo.

[0021] Preferably, R is phenyl optionally substituted by 1 to 3 halosubstituents.

[0022] More preferably, R is phenyl substituted by 1 or 2 substituentseach independently selected from fluoro and chloro.

[0023] Yet more preferably, R is phenyl substituted by 1 or 2 fluorosubstituents.

[0024] Most preferably, R is 2,4-difluorophenyl.

[0025] Preferably, R¹ is C₁-C₄ alkyl.

[0026] More preferably, R¹ is methyl or ethyl.

[0027] Most preferably, R¹ is methyl.

[0028] Preferably, “Het” is pyrimidinyl optionally substituted by 1 to 3substituents each independently selected from halo, oxo and benzyl.

[0029] More preferably, “Het” is pyrimidinyl optionally substituted by 1to 3 substituents each independently selected from fluoro, chloro, oxoand benzyl.

[0030] Yet more preferably, “Het” is pyrimidinyl substituted by 1 to 3substituents each independently selected from fluoro and chloro.

[0031] Preferred examples of “Het” include pyrimidin-4-yl,4-chloro-5-fluoropyrimidin-6-yl, 5-fluoropyrimidin-4-yl,2-chloro-5-fluoropyrimidin-6-yl, 2,4-dichloro-5-fluoropyrimidin-6-yl,4-chloropyrimidin-6-yl and 1-benzyl-5-fluoropyrimidin-6-on -4-yl.

[0032] Most preferably, “Het” is 4-chloro-5-fluoropyrimidin-6-yl.

[0033] Preferably, X is bromo or iodo.

[0034] Most preferably, X is bromo.

[0035] The compound of the formula (II) may be an enolisable ketone.Most preferably, the compound of formula (II) is1-(2,4-difluorophenyl)-2-(1H-1,2, 4-triazol-1-yl)ethanone.

[0036] Preferably the compound of the formula (III) is selected from6-(1-bromoethyl)-2,4-dichloro-5-fluoropyrimidine,6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine,6-(1-bromoethyl)-2-chloro-5-fluoropyrimidine,4-(1-bromoethyl)pyrimidine, 4-(1-bromoethyl)-6-chloropyrimidine,4-(1-bromoethyl) -5-fluoropyrimidine and1-benzyl-4-(1-bromoethyl)-5-fluoropyrimidin-6-one.

[0037] Most preferably, the compound of the formula (III) is6-(1-bromoethyl) -4-chloro-5-fluoropyrimidine.

[0038] The reaction is carried out in the presence of a suitable aproticorganic solvent such as tetrahydrofuran, toluene, 1,2-dimethoxyethane ormethylene chloride, or a mixture of two or more thereof. It is highlydesirable to dry the solvent before use to remove substantially alltraces of water. Drying can be achieved using a desiccant such asmagnesium sulphate, sodium sulphate or molecular sieves, by distillationfrom a metal such as lithium, sodium or potassium or by azeotropicdistillation.

[0039] The preferred solvent for the reaction is tetrahydrofuran.

[0040] It is also preferable to carry out the reaction under a dry,inert atmosphere such as by using dry nitrogen or argon gas.

[0041] The zinc used in the reaction may be zinc powder derived from acommercial source or it may be freshly generated in situ by thereduction of a zinc halide (e.g. zinc chloride) using lithium, sodium orpotassium (see, e.g., R. D. Rieke, Acc. Chem. Res., 10, 301 (1977)). Thezinc powder may be activated prior to use by stirring a slurry of thepowder for several hours in a suitable solvent, e.g. tetrahydrofuran.

[0042] Optionally, the reaction is carried out in the additionalpresence of lead.

[0043] The zinc powder obtained commercially may contain small amountsof lead as an impurity and the lead content can be up to about 2000parts per million (0.20 weight %) depending on the source. However, itis generally preferred to increase the lead content by adding lead inthe form of lead powder to the reaction mixture. Lead powder iscommercially available.

[0044] Preferably, when used, the amount of lead present in the reactionis 2000 ppm (0.2 wt %) or more relative to the amount of zinc present.More preferably, the amount of lead present is from 2000 to 100,000 ppm(0.2 to 10 weight %). Most preferably, the amount of lead present isabout 50,000 ppm (5 wt %).

[0045] Iodine is generally used in its commercially availablecrystalline form. It is suspected that its role in the reaction is inthe in situ generation of zinc iodide, possibly, when lead is alsopresent, in conjunction with lead (II) iodide as well, both of which mayfunction as catalysts.

[0046] Iodine, when used, may be introduced into the reaction vesselbefore, during or after the compounds of the formulae (II) and (III)have been added. Alternatively, it can be added in at least two stages,for example, one portion can be added to the reaction vessel before, andthe second portion can be added when, the compounds of the formulae (II)and (III) are added.

[0047] Suitable Lewis acids for use in the reaction include zincchloride, zinc bromide, zinc iodide, titanium (IV) isopropoxide,chlorotitanium triisopropoxide, titanium tetrachloride, trimethylborate, boron trifluoride (etherate), iron (III) chloride anddiethylaluminium chloride. Preferred Lewis acids are zinc bromide, zinciodide and, particularly, zinc chloride.

[0048] Iodine is preferably used rather than separately adding a Lewisacid.

[0049] Optionally, both iodine and a Lewis acid may be used in the aboveprocess.

[0050] The reaction may be carried out at from −15° C. to the refluxtemperature of the mixture. Preferably, it is carried out at from −10 to+30° C. and most preferably from −10° C. to +15° C.

[0051] The reaction almost certainly proceeds via formation of anorganozinc species derived from the in situ reaction of zinc with acompound of the formula (III) that is used as a starting material.

[0052] The reaction may be carried out by the following generalprocedure.

[0053] Iodine and/or a suitable Lewis acid are/is added to a stirredmixture of zinc, optionally lead, and a suitable aprotic organicsolvent. The mixture is cooled and a solution of a compound of theformula (II), a compound of the formula (III) and, optionally, furtheriodine in a suitable aprotic organic solvent is added, cooling themixture during the addition. The mixture is stirred for a further shortperiod before being warmed to room temperature. The reaction is quenchedby adding glacial acetic acid followed by water and conventional work-uptechniques can then be used in order to isolate the required product.

[0054] The process is optionally followed by formation of an acidaddition or a base salt of the product. Formation of an acid additionsalt is preferred and suitable salts include the hydrochloride,hydrobromide, hydroiodide, sulphate, nitrate, methanesulphonate,camphorsulphonate, R-(−)-10-camphorsulphonate,(+)-3-bromo-10-camphorsulphonate, (−)-3-bromo-8-camphorsulphonate,phosphate, para-toluenesulphonate and benzenesulphonate salts. Thehydrochloride salt is particularly preferred.

[0055] A compound of the formula (I) produced by the process of theinvention contains two or more asymmetric carbon atoms and thereforeexists in four or more stereoisomeric forms.

[0056] The reaction generally proceeds with high stereoselectivity infavour of the (2R,3S/2S,3R) enantiomeric pair of a compound of theformula (I), i.e.

[0057] where the asterixes (*) indicate the subject asymmetric carbonatoms.

[0058] Separation of diastereoisomers may be achieved by conventionaltechniques, e.g. by fractional crystallisation, chromatography orH.P.L.C. of a stereoisomeric mixture of a compound of the formula (I) ora suitable salt or derivative thereof. Resolution of enantiomers of acompound of the formula (I) may be achieved by H.P.L.C. of thecorresponding racemate using a suitable chiral support or by fractionalcrystallisation of the diastereoisomeric salts formed by reaction of thecorresponding racemate with a suitable optically active acid, e.g.R-(−)-10-camphorsulphonic acid.

[0059] The process is preferably used to prepare3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olfrom the starting materials1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone and6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine. High stereoselectivity canbe achieved in the reaction with, for example, a 9:1 molar ratio of the2R,3S/2S,3R to the 2R,3R/2S,3S enantiomeric pair being obtained if thereaction conditions are carefully controlled. In addition, for example,a 65% isolated total yield (as the hydrochloride salts) of all theenantiomers has been obtained.

[0060] The reaction product, which contains a far higher proportion of(2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olhydrochloride, can be reduced to provide(2R,3S/2S,3R)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olwhich can be resolved to provide(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olby the method described in European Patent Application Publicationnumber 0440372.

[0061] In a further aspect, the present invention provides a process forthe preparation of a compound of the formula:

[0062] , or an acid addition salt thereof, wherein R and R¹ are aspreviously defined for a compound of the formula (I) and R² is H orfluoro, which comprises the steps of:

[0063] (a) reaction of a compound of the formula:

[0064] wherein R is as defined for a compound of the formula (IV), witha compound of the formula:

[0065] wherein X is chloro, bromo or iodo, R¹ and R² are as previouslydefined for a compound of the formula (IV) and either R³ and R⁴ are eachindependently selected from chloro and bromo or one of R³ and R⁴ ischloro or bromo and the other is H, in the presence of zinc, iodineand/or a Lewis acid and an aprotic organic solvent, to provide acompound of the formula:

[0066] wherein R, R¹, R², R³ and R⁴ are as previously defined for thisstep (a);

[0067] (b) optionally converting the compound of the formula (IA) to anacid addition salt thereof;

[0068] (c) reduction of the compound of the formula (IA) or an acidaddition salt thereof to provide the compound of the formula (IV); and

[0069] (d) optionally converting the compound of the formula (IV) to anacid addition salt thereof.

[0070] The reactions conditions, including the preferred conditions,used for step (a) are as previously described for the preparation of acompound of the formula (I). Again, optionally, lead can also be presentin step (a).

[0071] The reduction in step (c) can be carried out under any conditionssuitable for the replacement of one or more of the R³/R⁴ groups whereR³/R⁴ is chloro or bromo by hydrogen.

[0072] The reduction may be carried out under conventional hydrogenationconditions using a suitable catalyst, e.g. palladium-on-charcoal,optionally in the presence of a suitable base, e.g. sodium acetate, andin a suitable solvent, e.g. ethanol, under a hydrogen atmosphere.

[0073] Preferably, the reduction is carried out under transferhydrogenation conditions using a suitable catalyst, e.g. palladium orrhodium, a suitable hydrogen donor, e.g. ammonium or potassium formate,and in a suitable solvent, e.g. methanol. The reaction is preferablycarried out at the reflux temperature of the solvent and under anitrogen atmosphere.

[0074] Examples of acid additions salts in step (b) include thehydrochloride, nitrate, methanesulphonate, p-toluenesulphonate,camphorsulphonate, R-(−)-10-camphorsulphonate,(+)-3-bromo-10-camphorsulphonate and (−)-3-bromo-8-camphorsulphonatesalts. Preferred acid addition salts in step (b) are the hydrochloride,methanesulphonate and p-toluenesulphonate salts.

[0075] A preferred acid addition salt in step (d) is theR-(−)-10-camphorsulphonate which may be used to resolve enantiomers ofthe compound of the formula (IV). A S-(+)-10-camphorsulphonate salt mayalso be generated and used for this purpose.

[0076] In this process for the preparation of a compound of the formula(IV):

[0077] (i) Preferably, R is phenyl optionally substituted by 1 to 3 halosubstituents.

[0078] More preferably, R is phenyl substituted by 1 or 2 substituentseach independently selected from fluoro and chloro.

[0079] Yet more preferably, R is phenyl substituted by 1 or 2 fluorosubstituents.

[0080] Most preferably, R is 2,4-difluorophenyl.

[0081] (ii) Preferably, R¹ is C₁-C₄ alkyl.

[0082] More preferably, R¹ is methyl or ethyl.

[0083] Most preferably, R¹ is methyl.

[0084] (iii) Preferably, X is bromo or iodo.

[0085] Most preferably, X is bromo.

[0086] (iv) Preferably, R² is fluoro.

[0087] (v) Preferably, R³ is chloro and R⁴ is H, R³ is H and R⁴ ischloro or R³ and R⁴ are both chloro.

[0088] (vi) Preferred compounds of the formula (IIIA) include:

[0089] 6-(1-bromoethyl)-2,4-dichloro-5-fluoropyrimidine,

[0090] 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine,

[0091] 6-(1-bromoethyl)-2-chloro-5-fluoropyrimidine and

[0092] 4-(1-bromoethyl)-6-chloropyrimidine.

[0093] (vii) Preferred compounds of the formula (IA) include:

[0094]3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,

[0095]3-(2-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,

[0096]3-(2,4-dichloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-oland

[0097]3-(4-chloropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,

[0098] and the acid addition salts thereof, particularly thehydrochloride, methanesulphonate and p-toluenesulphonate salts.

[0099] (viii) Preferred compounds of the formula (IV) include:

[0100]2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-oland

[0101]2-(2,4-difluorophenyl)-3-(pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,and the acid addition salts thereof, particularly the S-(+)- orR-(−)-10-camphorsulphonate salts.

[0102] The preparations of the starting materials used in the process ofthe present invention are conventional and appropriate reagents andreaction conditions for their preparation as well as procedures forisolating the desired products will be well known to those skilled inthe art with reference to literature precedents and the Preparationshereto.

[0103] The present invention also provides the following novelcompounds:

[0104] (i)(2R,3S)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol;

[0105] (ii) an acid addition salt of (2R,3S/2S,3R)- or(2R,3S)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-oland preferably a hydrochloride, nitrate, methanesulphonate,p-toluenesulphonate, camphorsulphonate, R-(−)-10-camphorsulphonate,(+)-3-bromo-10-camphorsulphonate or (−)-3-bromo-8-camphorsulphonatesalt;

[0106] (iii)3-(2,4-dichloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,or the (2R,3S/2S,3R)- or (2R,3S)-form thereof, or an acid addition saltof any thereof;

[0107] (iv)3-(2-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,or the (2R,3S/2S,3R)- or (2R,3S)-form thereof, or an acid addition saltof any thereof;

[0108] (v)3-(1-benzyl-5-fluoropyrimidin-6-on-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,or the (2R,3S/2S,3R)- or (2R,3S)-form thereof, or an acid addition saltof any thereof;

[0109] (vi)3-(4-chloropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,or the (2R,3S/2S,3R)- or (2R,3S)-form thereof, or an acid addition saltof any thereof;

[0110] (vii) 6-(1-bromoethyl)-2,4-dichloro-5-fluoropyrimidine;

[0111] (viii) 4-(1-bromoethyl)-6-chloropyrimidine;

[0112] (ix) 6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine;

[0113] (x) 1-benzyl-4-(1-bromoethyl)-5-fluoropyrimidin-6-one;

[0114] (xi) 6-(1-bromoethyl)-2-chloro-5-fluoropyrimidine;

[0115] (xii) 4-(1-bromoethyl)-5-fluoropyrimidine;

[0116] (xiii) 2-chloro-6-ethyl-5-fluoro-4-hydroxypyrimidine, ammoniumsalt.

[0117] The following Examples illustrate the process of the presentinvention:

EXAMPLE 19:1*(2R,3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-Chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olhydrochloride

[0118]

[0119] A stirred mixture of zinc powder (Britannia Alloys) (9.35 kg),lead (325 mesh, Aldrich) (0.47 kg) and tetrahydrofuran (53 L) was heatedunder reflux under a nitrogen atmosphere for 3 hours. The mixture wasthen cooled to 25° C. and stirring continued for 16 hours. A solution ofiodine (7.42 kg) in tetrahydrofuran (21 L) was added over 80 minutes andthe reaction temperature was allowed to rise to 45° C. during theaddition. The mixture was then cooled to from 0 to −5° C. A solution of1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (6.53 kg) and6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (see Preparation 1) (7.01kg) in tetrahydrofuran (53 L) was then added maintaining the reactiontemperature below +5° C. during the addition. The mixture was warmed to25° C. and glacial acetic acid (8.84 kg) and water (84 L) added. Thesolid metal residues were separated by decantation and 60 litres oftetrahydrofuran removed by distillation under reduced pressure. Ethylacetate (76 kg) was added and the distillation continued to remove 165litres of solvent. The mixture was cooled and extracted with ethylacetate (2×84 L), the combined extracts washed with a solution ofdisodium ethylenediaminetetraacetate dihydrate (3.22 kg) in water (161L), followed by saturated brine (30 L).

[0120] The ratio of the enantiomeric pairs contained in the organiclayer was determined by HPLC analysis using a 25 cm C18 Dynamax 60angstrom reverse phase column, a mobile phase consisting of 65:35, byvolume, acetonitrile:water and a flow rate of 1 ml/min. The detector wasset at 254 nm. This analysis showed a 9:1 molar ratio of the 2R,3S/2S,3R(RT=5.53 min.) to the 2R,3R/2S,3S (RT=4.47 min.) enantiomeric pair ofthe free base of the title compound.

[0121] The organic layer was concentrated to a volume of 56 litres and asolution of hydrogen chloride (1.2 kg) in isopropanol (6 L) added at 25°C. The title compound precipitated as a solid. This was collected byfiltration, washed with ethyl acetate (5 litres) and dried (7.89 kg,65%), m.p. 126-130° C.

EXAMPLE 210.3:1*(2R,3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-Chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

[0122]

[0123] A solution of iodine (2.25 g) in tetrahydrofuran (6 ml) was addeddropwise to a stirred slurry of zinc (Britannia Alloys) (3.00 g) andlead (0.15 g) in tetrahydrofuran (19 ml) under a nitrogen atmosphere at25° C. The reaction temperature was allowed to rise during the addition.The mixture was then cooled to 2° C. A solution of1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (2.00 g),6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (see Preparation 1) (2.84g) and iodine (0.02 g) in tetrahydrofuran (16 ml) was added dropwiseover 10 minutes. The reaction temperature was limited to a maximum of16° C. during the addition by cooling. Further cooling was then appliedto obtain a temperature below +5° C. The reaction was stirred below +5°C. for 30 minutes. A sample of the reaction mixture was taken andsubjected to HPLC analysis according to the conditions set out inExample 1. The analysis showed a 10.3:1 molar ratio of the 2R,3S/2S,3Rto the 2R,3R/2S,3S enantiomeric pair of the title compound. The yield ofthe 2R,3S/2S,3R enantiomeric pair was calculated to be 90% using aninternal standard.

EXAMPLE 311.2:1*(2R,3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-Chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olhydrochloride

[0124]

[0125] Zinc dust (Britannia Alloys) (37.9 g), lead (1.9 g) and zincchloride (16.2 g) were stirred at 2° C. under an atmosphere of nitrogenin tetrahydrofuran (320 ml). A solution of1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (26.6 g) and6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (see Preparation 1) (40 g)in tetrahydrofuran (215 ml) was added dropwise over 5 minutes. Thereaction temperature was kept below 12° C. with applied cooling. Thereaction was stirred below +10° C. for 3 hours and at ambienttemperature overnight. Completion of the reaction was ascertained byHPLC using the conditions set out in Example 1. The assay showed a 6.7:1molar ratio of the 2R,3S/2S,3R to the 2R,3R/2S,3S enantiomeric pair ofthe free base of the title compound. Glacial acetic acid (8 g) and water(400 ml) were then added maintaining the reaction temperature below 25°C. and the mixture stirred for 15 minutes. The solid metal residues wereremoved by decantation. The mixture was basified to pH 10 usingsaturated aqueous sodium carbonate solution (600 ml) and adjusted backto pH 8.0 with 5M aqueous hydrochloric acid solution (15 ml). The solidswere filtered off and the tetrahydrofuran removed by distillation underreduced pressure. The mixture was extracted with ethyl acetate (2×400ml). The organic phases were combined and washed with water (400 ml), 2%weight/volume solution of disodium ethylenediaminetetraacetic acid inwater (800 ml), followed by water (400 ml). The ethyl acetate layer wasconcentrated to an oil. The oil was dissolved in ethyl acetate (225 ml)and a 5.75M solution of hydrogen chloride in isopropanol (20 ml) wasadded. The slurry was granulated at 20° C. for 1 hour and at 0° C. for 1hour. The crude title compound was isolated by filtration and driedunder reduced pressure at 50° C. (39.9 g). HPLC analysis according tothe conditions set out in Example 1 showed the proportion of the titlecompound in the crude product to be 93.9% by weight.

EXAMPLE 410.2:1*(2R,3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-Chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

[0126]

[0127] A mixture of zinc dust (Britannia Alloys) (3.00 g) andtetrahydrofuran (20 ml) was stirred overnight at room temperature andthen a solution of iodine (2.27 g) in tetrahydrofuran (6 ml) was added,dropwise, over 3 minutes. The temperature of the reaction rose to about45° C. during the addition and it was cooled to 5-10° C. before theaddition of a solution of1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (2.00 g) and6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (see Preparation 1) (2.9 g)in tetrahydrofuran (16 ml) (using the same dropping funnel used for theabove iodine addition) over a 40 minute period.

[0128] After two hours stirring, a sample of the reaction mixture wastaken and subjected to HPLC analysis using the conditions set out inExample 1. By comparison with reference standards (see Example 1), thereaction mixture was shown to contain a 10.2:1 molar ratio of the2R,3S/2S,3R to the 2R,3R/2S,3S enantiomeric pair of the title compound.The total yield was calculated to be about 72%.

[0129] Further examination after one hour showed little deviation fromthe above position. The reaction was terminated at this point and notfurther evaluated.

EXAMPLE 59.4:1*(2R,3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-Chloro-5-fluoropyrimidin-6yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

[0130]

[0131] A solution of iodine (2.04 g) in tetrahydrofuran (6 ml) was addeddropwise to a stirred slurry of zinc (Brittania Alloys) (3.00 g) intetrahydrofuran (19 ml) under a nitrogen atmosphere at 25° C. Thereaction temperature was allowed to rise during the addition. Themixture was then cooled to 2° C. A solution of1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (2.00 g),6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (see Preparation 1) (3.00g) and iodine (0.23 g) in tetrahydrofuran (16 ml) was added dropwiseover 10 minutes, maintaining the temperature below +5° C. with appliedcooling. The reaction was stirred below +5° C. for 30 minutes. A sampleof the reaction mixture was taken and subjected to HPLC analysisaccording to the conditions set out in Example 1. The analysis showed a9.4:1 molar ratio of the 2R,3S/2S,3R to the 2R,3R/2S,3S enantiomericpair of the title compound. The yield of the 2R,3S/2S,3R enantiomericpair was calculated to be 77% using an internal standard.

EXAMPLE 610.2:1*(2R,3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-Chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

[0132]

[0133] A solution of iodine (2.20 g) in tetrahydrofuran (6 ml) was addeddropwise to a stirred slurry of zinc (Britannia Alloys) (3.00 g) intetrahydrofuran (19 ml) under a nitrogen atmosphere at 25° C. Thereaction temperature was allowed to rise during the addition. Themixture was then cooled to 2° C. A solution of1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (2.00 g) and6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (see Preparation 1) (2.84g) in tetrahydrofuran (16 ml) was added dropwise over 10 minutes. Duringthe first 2 minutes of this addition a solution of iodine (0.07 g) intetrahydrofuran (4 ml) was also added. Cooling was applied to maintainthe reaction temperature below +5° C. The reaction was stirred below +5°C. for 30 minutes. A sample of the reaction mixture was taken andsubjected to HPLC analysis according to the conditions set out inExample 1. The analysis showed a 10.2:1 molar ratio of the 2R,3S/2S,3Rto the 2R,3R/2S,3S enantiomeric pair of the title compound. The yield ofthe 2R,3S/2S,3R enantiomeric pair was calculated to be 87% using aninternal standard.

EXAMPLE 764:1*(2R,3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-Chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olhydrochloride

[0134]

[0135] A solution of iodine (20.52 g) in tetrahydrofuran (65 ml) wasadded dropwise to a stirred slurry of zinc dust (28.6 g) intetrahydrofuran (160 ml) under a nitrogen atmosphere at 20° C. Thereaction temperature was allowed to rise to 25° C. The mixture was thencooled to from 0° C. to 5° C. A solution of1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (20.0 g),6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine (see Preparation 1) (23.6g) and iodine (2.28 g) in tetrahydrofuran (160 ml) was added dropwiseover 75 minutes, maintaining a reaction temperature of from 0° C. to +5°C. with applied cooling. The reaction was stirred below +5° C. for 30minutes. Completion of the reaction was ascertained by HPLC using theconditions set out in Example 1. The assay showed the stoichiometricyield of the 2R,3S/2S,3R enantiomeric pair to be 88%. Glacial aceticacid (5.4 ml) and water (260 ml) were then added maintaining thetemperature below 25° C. The solid metal residues were removed bydecantation. The mixture was basified to pH 10 using saturated aqueoussodium carbonate solution (180 ml) and then adjusted to pH 8.0 with 5Maqueous hydrochloric acid solution. The solids were filtered off and thetetrahydrofuran removed by distillation under reduced pressure. Ethylacetate (260 ml) was added and the mixture stirred for 10 minutes. Theorganic layer was separated and the aqueous phase was extracted withethyl acetate (86 ml). The organic phases were combined and washed witha 2% weight/volume solution of disodium ethylenediaminetetraacetic acidin water (286 ml), water (139 ml) and saturated brine (52 ml). The ethylacetate layer was concentrated to a volume of 150 ml. A solution ofsulphosalicyclic acid (1.86 g) in isopropanol (5 ml) was added and theslurry granulated at 20° C. for 2 hours. The solid was filtered off andwashed with ethyl acetate (2×3 ml). A 6M solution of hydrogen chloridein isopropanol (1.1 molar ratio relative to the amount of product and1(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone in the filtrate)was added to the filtrate and the slurry granulated at 25° C. for 2hours and at from 0 to 2° C. for a further hour. The crude titlecompound was isolated by filtration, washed with ethyl acetate (20 ml)and dried under reduced pressure at 50° C. The mass yield was 30 g. HPLCanalysis according to the conditions set out in Example 1 showed theproduct to contain a 75.7% by weight stoichiometric yield of the2R,3S/2S,3R enantiomeric pair of the title compound.

EXAMPLE 8 5.5:1*(2R,3S/2S,3R)-:(2R,3R/2S,3S)-3-(2,4-Dichloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

[0136]

[0137] A stirred mixture of zinc powder (Britannia Alloys) (78.6 g),lead powder (Aldrich) (3.9 g) and tetrahydrofuran (450 ml) was kept at20° C. for 17 hours then treated with a solution of iodine (153 g) intetrahydrofuran (450 ml), keeping the temperature below 45° C. usingcooling. The mixture was then cooled to −30° C. and a solution of1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (134.7 g) and6-(1-bromoethyl)-2,4-dichloro-5-fluoropyrimidine (see Preparation 3)(82.4 g) in tetrahydrofuran (300 ml) added, keeping the temperaturebetween −3 and −5° C. The mixture was warmed to 30° C. and kept at thistemperature for 2 hours, then quenched with glacial acetic acid (150 ml)and water (750 ml). The supernatant liquor was decanted from the metalresidues and the tetrahydrofuran removed by concentration under reducedpressure. Ethyl acetate (2.5 L) was added and the mixture basified byadding saturated aqueous sodium carbonate solution (1.5 L). The mixturewas granulated at 20° C. for 30 minutes and the precipitated zinccarbonate removed by filtration. The organic layer in the filtrate wasseparated, washed with water (2×2.0 L) and concentrated under reducedpressure. The solution obtained was treated with a solution of5-sulfosalicylic acid dihydrate (107.5 g) in isopropanol (215 ml). Aftergranulating for 1 hour at 20° C., the precipitated1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone sulfosalicylatewas removed by filtration. The filtrate was washed with 5% w/v aqueousdisodium ethylenediaminetetracetate dihydrate solution (2×500 ml), water(500 ml) and then concentrated under reduced pressure to give the crudeproduct as a syrup (123.8 g).

[0138] HPLC analysis using the conditions set out in Example 1 showedthe product to contain a 5.5:1 molar ratio of the 2R,3S/2S,3R (RT=7.1min.) to the 2R,3R/2S,3S (RT=5.6 min.) enantiomeric pair of the titlecompound.

[0139]¹H-NMR (300 MHz, CDCl₃): δ=1.06 (d,3H), 3.95 (q,1H), 4.34 (d,1H),4.70 (d,1H), 5.55 (s,br.,1H), 6.65-6.80 (m,2H), 7.45-7.56 (m,1H), 7.55(s,1H), 7.93 (s,1H) ppm.

EXAMPLE 99.2:1*(2R,3S/2S,3R)-:(2R,3R/2S,3S)-3-(1-Benzyl-5-fluoropyrimidin-6-on-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

[0140]

[0141] A stirred mixture of zinc dust (Pasminco) (573 mg), lead powder(29 mg) and tetrahydrofuran (6 ml) was kept at room temperature for 18hours and then a solution of iodine (370 mg) in tetrahydrofuran (2 ml)was added. A solution of1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone (653 mg) and1-benzyl-4-(1-bromoethyl)-5-fluoropyrimidin-6-one (see Preparation 5)(1.00 g) in tetrahydrofuran (7 ml) was then added, dropwise, to themixture over 10 minutes. The reaction was heated to about 40° C. for 1hour then cooled and quenched with glacial acetic acid (1 ml) and water(10 ml). The mixture was partitioned between water and ethyl acetate,the organic layer separated and washed with an aqueous solution ofpotassium bicarbonate followed by brine, then dried (MgSO₄) andconcentrated under reduced pressure. The residue was chromatographed onsilica gel eluting with hexane:ethyl acetate (solvent gradient of 4:1 to1:1 to 0:1, by volume, used) to provide the product as a white solid(519 mg, 39%).

[0142] HPLC analysis using the conditions set out in Example 1 showedthe product to contain a 9.2:1 molar ratio of the 2R,3S/2S,3R (RT=3.78min.) to the 2R,3R/2S,3S (RT=5.28 min.) enantiomeric pair of the titlecompound.

[0143]¹H-NMR (300 MHz, CDCl₃): δ=1.02 (d,3H), 3.91 (q,1H), 4.30 (d,1H),4.78 (d,1H), 5.12 (d,1H), 5.19 (d,1H), 5.95 (s,1H), 6.72-6.86 (m,2H),7.30-7.56 (m,7H), 7.89 (s,1H), 8.00 (s,1H) ppm.

EXAMPLE 1012.5:1*(2R,3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-chloropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

[0144]

[0145] A mixture of zinc dust (Britannia Alloys) (249 g), lead powder(12.3 g) and tetrahydrofuran (760 ml) was stirred overnight at roomtemperature and then a solution of iodine (203.4 g) in tetrahydrofuran(650 ml) was added, dropwise. The temperature of the reaction rose toabout 45° C. during the addition. It was then cooled to 5-10° C. and asolution of 1-(2,4-difluorophenyl)-2-(1H-1,2,4-triazol-1-yl)ethanone(199 g), 4-(1-bromoethyl)-6-chloropyrimidine (293 g of the crude productof Preparation 6: calculated to contain 217 g of this pyrimidine) andiodine (22.6 g) in tetrahydrofuran (1600 ml) was added over 30 minuteskeeping the temperature below 55° C. After 1 hour, a sample of thereaction mixture was taken and subjected to HPLC analysis using theconditions set out in Example 1. The molar ratio of the 2R,3S/2S,3R(retention time 4.23 minutes) to the 2R,3R/2S,3S (retention time 3.4minutes) enantiomeric pair was determined to be 12.5:1.

[0146] The reaction was cooled to 20° C. and quenched by the addition ofglacial acetic acid (56 g) and water (180 ml). The zinc residues wereremoved by filtration and the solution treated with aqueous sodiumcarbonate solution until the mixture reached pH 10. The pH was thenlowered to 7.5 using dilute aqueous hydrochloric acid solution and thezinc carbonate precipitated was removed by filtration. The solution wasconcentrated under reduced pressure to remove most of thetetrahydrofuran solvent to provide an aqueous slurry that was extractedusing dichloromethane (2×500 ml). The organic phases were combined andwashed with 5% w/w aqueous ethylenediaminetetraacetic acid, disodiumsalt solution (2×500 ml). After concentrating the organic phase underreduced pressure, the residue was crystallised from isopropyl alcohol(2.5 litres) and the solid collected by filtration. After drying at 50°C. under reduced pressure, the product (140 g) was analysed by HPLC andshown to contain 91% by weight of the (2R,3S/2S,3R) enantiomeric pair ofthe title compound.

[0147]¹H-NMR (300 MHz, CDCl₃): δ=1.1 (d,3H), 3.65 (q,1H), 4.15 (d,1H),4.8 (d,1H), 6.15 (s,1H), 6.8 (m,2H), 7.5 (s,1H), 7.55 (m,1H), 7.65(s,1H), 7.9 (s,1H), 8.9 (s,1H) ppm.

[0148] The following Preparations illustrate the preparation of certainstarting materials used in the preceding Examples together with thefurther processing of certain compounds of these Examples:

PREPARATION 1 6-(1-Bromoethyl)-4-chloro-5-fluoropyrimidine

[0149]

[0150] (i) 2,4-Dichloro-5-fluoropyrimidine

[0151] A stirred mixture of 5-fluorouracil (111.5 kg) and phosphorusoxychloride (394.6 kg) was heated to 95° C. and N,N-dimethylaniline (207kg) added over 1 hour during which time an exotherm was noted. Themixture was maintained at 95° C. for 15 hours then cooled to roomtemperature and cautiously quenched into ice-cooled 3N aqueoushydrochloric acid solution (450 L) over 4 hours, maintaining thetemperature below 30° C. during this operation. The mixture wasextracted with dichloromethane (2×390 L), the combined extracts washedwith water (280 L) until the aqueous washings reached pH7 andconcentrated under reduced pressure. The residue taken up indimethoxyethane (190 L) and the solution of the product used directly inthe next step.

[0152]¹H-NMR (300 MHz, CDCl₃): δ=8.5 (s,1H) ppm.

[0153] (ii) 2,4-Dichloro-6-ethyl-5-fluoropyrimidine

[0154] To a stirred mixture of magnesium turnings (12.1 kg) intetrahydrofuran (161 L) was added a solution of bromoethane (54.3 kg) intetrahydrofuran (53 L) maintaining the reaction temperature below 50° C.during the addition. The solution of the Grignard reagent was cooled to0° C. and a solution of the compound of part (i) (56 kg) indimethoxyethane (170 L) added, maintaining the reaction temperaturebelow 15° C. during the addition. The reaction was stirred for 1 hour at15° C. and cooled to 0° C. A solution of triethylamine (34 kg) intetrahydrofuran (70 L) was added, maintaining the reaction temperatureat about 5° C., followed by a solution of iodine (85 kg) intetrahydrofuran (256 L), maintaining the reaction temperature below 15°C. The reaction was then quenched with water (840 L), maintaining thereaction temperature below 25° C. The pH was adjusted to 1 using 5Naqueous hydrochloric acid solution (50 L) and the mixture extracted withtoluene (1×490 L followed by 1×210 L). The combined organic layers werewashed with 2% w/w aqueous sodium metabisulphite solution (700 L) thenwater (700 L) added and the remaining tetrahydrofuran removed bydistillation under reduced pressure. The mixture was cooled, the organiclayer separated, washed with water (425 L) and then concentrated underreduced pressure to provide the product as an oil (50 kg).

[0155] (iii) 2-Chloro-6-ethyl-5-fluoro-4-hydroxypyrimidine, AmmoniumSalt

[0156] A mixture of the compound of part (ii) (40 kg) and water (10 kg)was heated to 90° C. and 4N aqueous sodium hydroxide solution (127 L)added. Heating was continued at 80° C. for 30 minutes and then themixture was cooled to 25° C. The mixture was washed with toluene (124L), the aqueous layer separated and dichloromethane (162 L) addedthereto. To this mixture was added concentrated hydrochloric acid untilpH1 was achieved. The organic layer was separated and the aqueous layerextracted with dichloromethane (162 L). The combined organic layers weretreated with activated carbon (Norit-trade mark) (8.8 kg). The solutionwas filtered and the filtrate treated with concentrated aqueous ammoniasolution until pH9 was achieved. The product precipitated as a solid andwas collected by filtration (34 kg), m.p. 125-131° C.

[0157] (iv) 6-Ethyl-5-fluoro-4-hydroxypyrimidine

[0158] To a mixture of the compound of part (iii) (34 kg), ethanol (170L) and water (5 kg) was added 5% w/w palladium-on-carbon (50% w/w watercontent) (3.4 kg) and the mixture hydrogenated at 50° C. and 345 kPa (50psi) until completion of the reaction. Water (10.5 L) was added and thecatalyst removed by filtration. The filtrate was concentrated underreduced pressure to a small volume and extracted with dichloromethane(2×58 L). The combined organic extracts were concentrated under reducedpressure and toluene (150 L) added. The mixture was concentrated underreduced pressure to 50 L in volume, toluene (50 L) added and cooled to4° C. for 4 hours. The precipitated product was collected by filtration,washed with toluene (10 L) and dried (Yield=20 kg), m.p. 112-4° C.

[0159]¹H-NMR (300 MHz, CDCl₃): δ=1.25 (m,3H), 2.73 (m,2H), 8.00 (s,1H)ppm.

[0160] (v) 4-Chloro-6-ethyl-5-fluoropyrimidine

[0161] To a mixture of the compound of part (iv) (40 kg),dichloromethane (120 L) and triethylamine (28.4 g) was slowly addedphosphorus oxychloride (47.2 kg) over 3 hours maintaining the reactiontemperature below 40° C. during the addition. The mixture was heatedunder reflux for 5 hours, cooled to 25° C. and cautiously quenched into3N aqueous hydrochloric acid solution (176 L), maintaining thetemperature below 20° C. during this operation. The layers wereseparated, the aqueous phase extracted with dichloromethane (50 L) andthe combined organic layers washed with water (50 L). The organic layerwas concentrated under reduced pressure to provide the product as an oil(40.69 kg).

[0162]¹H-NMR (300 MHz, CDCl₃): δ=1.30 (t,3H), 2.87 (q,2H), 8.65 (s,1H)ppm.

[0163] (vi) 6-(1-Bromoethyl)-4-chloro-5-fluoropyrimidine

[0164] A stirred mixture of the compound of part (v) (38.5 kg),azoisobutyronitrile (AIBN) (1.92 kg), N-bromosuccinimide (49 kg) anddichloromethane (198 L) was heated under reflux under nitrogen for 12hours. The mixture was cooled to 25° C. and water (239 L) added. Thelayers were separated and the aqueous layer extracted withdichloromethane (120 L). The combined organic layers were washed with asolution of sodium metabisulphite (22.8 kg) in water (239 L), followedby water (239 L). The organic layer was concentrated under reducedpressure, toluene (240 L) was added and the resulting solutionconcentrated under reduced pressure to give the product as an oil (61.7kg).

[0165]¹H-NMR (300 MHz, CDCl₃): δ=2.08 (d,3H), 5.35 (q,1H), 8.80 (s,1H)ppm.

PREPARATION 2(2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

[0166]

[0167] (i)(2R,3S/2S,3R)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

[0168] A stirred mixture of the product obtained by the procedure ofExample 1 (26.5 kg), dichloromethane (400 L) and water (184 L) wasadjusted to pH 11 using 40% w/w aqueous sodium hydroxide solution (10L). The organic layer was separated, washed with a solution of disodiumethylenediaminetetracetate dihydrate (8.74 kg) in water (183.5 L)followed by water (184 L) and then concentrated under reduced pressureto an oil. This was dissolved in ethanol (134 L), sodium acetate (8 kg)and 5% w/w palladium-on-carbon (50% w/w water content) (3.34 kg) addedand the mixture hydrogenated at 103 kPa (15 psi) and 25° C. untilcompletion of the reaction. The catalyst was removed by filtration andthe filtrate concentrated to a volume of 51 litres. Dichloromethane (152L) and water (152 L) were added and the pH adjusted to 11 using 40% w/waqueous sodium hydroxide solution. The layers were separated and theaqueous layer extracted with dichloromethane (61 L). The combinedorganic extracts were washed with water (61 L), concentrated underreduced pressure, isopropanol (70 L) added and concentrated to a volumeof 62 L. The mixture was granulated for 3 hours at 20° C., collected byfiltration, washed with isopropanol (2×5 L) and dried to provide thetitle compound as the major enantiomeric pair in the product (19 kg),m.p. 127° C.

[0169] (ii)(2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-25triazol-1-yl)butan-2-ol

[0170] To a solution of the compound of part (i) (18.93 kg) in acetone(426 L) was added a solution of R-(−)-10-camphorsulphonic acid (12.57kg) in methanol (142 L) and the mixture heated under reflux until ahomogenous solution was obtained. The solution was cooled to 20° C. andgranulated overnight. The solid was collected by filtration, washed withacetone (9.35 kg) and dried to provide(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olR-(−)-10-camphorsulphonate as a white solid (12.3 kg).

[0171] The above camphorsulphonate salt (12.3 kg) was taken up indichloromethane (61.5 L) and water (61.5 L) and the pH adjusted to 11 byadding 40% w/w aqueous sodium hydroxide solution (2.5 L). The layerswere separated and the aqueous layer extracted with dichloromethane (14L). The combined organic extracts were washed with water (3×45 L),filtered and the solvent removed by distillation under reduced pressure.Isopropanol (30 L) was added and the distillation continued until avolume of 22 litres was achieved. The mixture was cooled to 0° C. andgranulated for 2 hours. The product was collected by filtration andwashed with isopropanol (2×4 L) to provide the title compound as a whitesolid (7.6 kg).

PREPARATION 3 6-(1-Bromoethyl)-2,4-dichloro-5-fluoropyrimidine

[0172]

[0173] (i) 2,4-Dichloro-6-ethyl-5-fluoropyrimidine

[0174] To a stirred mixture of magnesium turnings (90.4 g) intetrahydrofuran (1.04 L) was added a solution of bromoethane (407 g) intetrahydrofuran (1.04 L), maintaining the reaction temperature between35-40° C. The solution of the Grignard reagent was stirred for 30minutes at 20° C., cooled to 0° C. and a solution of the compound ofPreparation 1(i) (420 g) in dimethoxyethane (600 ml) was added keepingthe reaction temperature below 15° C. The mixture was stirred for 1 hourat 15° C. then cooled to 0° C. A solution of triethylamine (254 g) intetrahydrofuran (510 ml) was added at 5° C., followed by a solution ofiodine (632 g) in tetrahydrofuran (1.92 L), keeping the temperaturebelow 15° C. The reaction was quenched with water (6 L) keeping thetemperature below 25° C. The mixture was acidified to pH1 with 5Naqueous hydrochloric acid solution and extracted with ethyl acetate (2×6L). The combined organic extracts were washed with a 10% w/v aqueoussodium metabisulphite solution (12 L). Water (4 L) was added and most ofthe organic solvent removed by evaporation under reduced pressure. Thelayers were separated and the aqueous layer extracted with ethyl acetate(2 L). The combined organic extracts were treated with glacial aceticacid (400 ml) and concentrated under reduced pressure at 80° C. Themixture was cooled to 20° C. and the oil partitioned betweendichloromethane (3 L) and 1N aqueous sodium hydroxide solution (3 L).The organic layer was separated, washed with water (3.0 L) andconcentrated under reduced pressure to provide the product as an oil(402 g).

[0175]¹H-NMR (300 MHz, CDCl₃): δ=1.33 (t,3H), 2.87 (dq,2H) ppm.

[0176] (ii) 6-(1-Bromoethyl)-2,4-dichloro-5-fluoropyrimidine

[0177] A mixture of the compound of part (i) (400 g), N-bromosuccinimide(730 g), azoisobutyronitrile (33.7 g), bromine (65.5 g) and water (6.4L) was heated at 80-85° C. for 5 hours. Further N-bromosuccinimide (183g) was added, heating continued for 2 hours then furtherazoisobutyronitrile (33.7 g) added. After heating for 2 hours at 85° C.further azoisobutyronitrile (33.7 g) was added and heating continued for3 hours. The reaction was cooled, diluted with water (4 L) and extractedwith dichloromethane (2×3 L). The combined organic extracts were washedwith a solution of sodium metabisulphate (600 g) in water (2.5 L),followed by water (3 L). The solvent was removed by evaporation underreduced pressure, toluene (1.0 L) added and the solution concentratedunder reduced pressure to give the product as an oil (534 g).

[0178]¹H-NMR (300 MHz, CDCl₃): δ=2.05 (d,3H), 5.06 (q,1H) ppm.

PREPARATION 4(2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

[0179]

[0180](2R,3S/2S,3R)-2-(2.4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

[0181] A stirred mixture of the product obtained by the procedure ofExample 8 (123.8 g), sodium acetate (27.4 g), 5% w/w palladium-on-carbon(50% w/w water content) (18.6 g) and ethanol (1.24 L) was hydrogenatedat 50° C. and 345 kPa (50 psi) for 19 hours. The reaction was cooled to25° C. and the catalyst filtered off and washed with ethanol (100 ml).The filtrate was concentrated under reduced pressure to dryness and theresidue partitioned between dichloromethane (1.0 L) and 10% w/v aqueouspotassium bicarbonate solution (1.0 L). The organic layer was separatedand washed with water, then evaporated under reduced pressure to drynessto provide the title compound as the major enantiomeric pair in theproduct. This was used directly in the next step.

[0182]¹H-NMR (300 MHz, d₆-DMSO): δ=1.10 (d,3H), 3.90 (q,1H), 4.33(d,1H), 4.80 (d,1H), 6.87-6.93 (m,1H), 7.10-7.20 (m,1H), 7.21-7.34(m,1H), 7.60 (s,1H), 8.21 (s,1H), 8.82 (s,1H), 9.02 (s,1H) ppm.

[0183] (ii)(2R,3S)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

[0184] The product of part (i) was taken up in acetone (383 ml) and asolution of R-(−)-camphor-10-sulphonic acid (42.1 g) in acetone (300 ml)added. The mixture was granulated at 20° C. for 18 hours and then cooledto 0° C. for 1 hour. The solid was filtered off and washed with coldacetone (100 ml) then dried to provide a crude camphorsulphonate product(35.4 g).

[0185] HPLC analysis (25cm×4.6 mm C18 Dynamax 60 angstrom reverse phasecolumn, mobile phase=65:35, by volume, acetonitrile:water, flow rate 1ml/min.) showed this material to be 91% chemically pure and to contain a63:37 molar ratio of the 2R,3S- to the 2S,3R-enantiomeric pair.

[0186] This partially resolved salt (34 g) was dissolved in a mixture ofmethanol (110 ml) and acetone (329 ml) which was heated under reflux.The solution was cooled to 20° C. slowly and granulated overnight. Thesolid was collected by filtration, washed with acetone (50 ml) and driedto provide(2R,3S)-2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olR-(−)-camphor-10-sulphonate as white crystals (17.1 g), m.p. 187° C.HPLC analysis showed this material to be 100% optically pure.

[0187] This salt (17 g) was partitioned between dichloromethane (85 ml)and water (85 ml) and the pH adjusted to 11 by adding 40% w/w aqueoussodium hydroxide solution. The layers were separated and the aqueousphase extracted with dichloromethane (20 ml). The combined organicextracts were washed with water (2×80 ml), filtered and the solventremoved by evaporation under reduced pressure. Isopropanol (26 ml) wasadded, the solution cooled to 0° C. and granulated for 1 hour. The solidwas collected by filtration, washed with cold isopropanol (5 ml) anddried under reduced pressure at 50° C. to provide the product (8.4 g),m.p. 133° C.

[0188]¹H-NMR (300 MHz, d₆-DMSO): δ=1.10 (d,3H), 3.90 (q,1H), 4.33(d,1H), 4.80 (d,1H), 6.87-6.93 (m,1H), 7.10-7.20 (m,1H), 7.21-7.34(m,1H), 7.60 (s,1H), 8.21 (s,1H), 8.82 (s,1H), 9.02 (s,1H) ppm.

PREPARATION 5 1-Benzyl-4-(1-bromoethyl)-5-fluoropyrimidin-6-one

[0189]

[0190] (i) 1-Benzyl-4-ethyl-5-fluoropyrimidin-6-one

[0191] Sodium hydride (60% w/w dispersion in oil, 928 mg) was trituratedwith hexane then dimethylformamide (30 ml) added. To this mixture wasadded the compound of Preparation 1(iv) (3 g) and, following cessationof the effervescence, benzyl bromide (2.51 ml). The mixture was stirredfor 1 hour then quenched with water. The mixture was partitioned betweendiethyl ether and water, the ether layer separated and washedsuccessively with dilute sodium hydroxide solution, brine and water,then concentrated under reduced pressure to provide the required productas white crystals (4.04 g). LRMS m/z =232.9(m)⁺.

[0192]¹H-NMR (300 MHz, CDCl₃): δ=1.22 (t,3H), 2.63 (dq,2H), 5.14 (s,2H),7.32-7.40 (m,5H), 7.93 (s,1H) ppm.

[0193] (ii) 1-Benzyl-4-(1-bromoethyl)-5-fluoropyrimid-6-one

[0194] A mixture of the compound of Preparation 5(i) (2 g),N-bromosuccinimide (1.76 g), azoisobutyronitrile (71 mg) anddichloromethane (20 ml) was heated under reflux under nitrogen for 20hours. The reaction was cooled, washed successively with a diluteaqueous solution of sodium metabisulphite, water and then brine, thendried (MgSO₄) and concentrated under reduced pressure. The residue waschromatographed on silica gel eluting with ethyl acetate:hexane (1:7, byvolume) to provide the product as a white syrup (1.60 g). LRMSm/z=310.9/312.9(m)⁺.

[0195]¹H-NMR (300 MHz, CDCl₃): δ=1.94 (d,3H), 5.07 (d,1H), 5.17 (d,1H),5.30 (q,1H), 7.30-7.41 (m,5H), 8.00 (s,1H) ppm.

PREPARATION 6 4-(1-Bromoethyl)-6-chloropyrimidine

[0196]

[0197] (i) 4-Ethyl-6-hydroxypyrimidine

[0198] Formamidine acetate (500 g) and methyl 3-oxopentanoate (500 g)were added to a solution of sodium methoxide (500 g) in methanol (4 L)at 20° C. and the mixture stirred for 15 hours. Water (1 L) and aceticacid (500 ml) were added to give a pH of 7. The solvent was removed byevaporation under reduced pressure and the aqueous residue was dilutedwith water (1 L) and extracted with methyl ethyl ketone (4×2.5 L). Theorganic phases were combined and concentrated by evaporation underreduced pressure to give an orange syrup. The syrup was dissolved inethyl acetate (1 L) and the solution stirred for 15 hours to give asolid. The solid was collected by filtration, washed with ethyl acetate(200 ml, at 10° C.) and dried at 50° C. under reduced pressure toprovide the title compound (183 g). After concentrating the motherliquors under reduced pressure, diethyl ether (3 L) was added to providea solid. This was solid was collected by filtration, washed withtert-butyl methyl ether (200 ml) and dried at 50° C. under reducedpressure to provide a second crop of the title compound (195 g). Thetotal yield of the title compound was approximately 79%.

[0199]¹H-NMR (300 MHz. D₂O): δ=1.02-1.12 (m,3H), 1.89 (s,1H), 2.41-2.55(m,2H), 6.21 (s,1H), 8.16 (s,1H) ppm.

[0200] (ii) 4-Chloro-6-ethylpyrimidine

[0201] The product from Preparation 6(i) (348 g) was slurried indichloromethane (2.5 L) and triethylamine (284 g) added. Phosphorusoxychloride (473 g) was added to the mixture and an exotherm resultedtaking the reaction mixture to the reflux temperature. The refluxtemperature was maintained for 4 hours and the reaction was then cooledto 20° C. and quenched into 1N aqueous hydrochloric acid solution (2.2L) with applied cooling (maintaining the reaction temperature at about10° C.). After separating the organic phase, the aqueous layer wasextracted with dichloromethane (1 L). The organic phases were combinedand washed with water (2×3 L). The solution was concentrated underreduced pressure to give the product (272 g, 80% purity by ¹H-NMRcalculation) as a dark oil.

[0202]¹H-NMR (300 MHz. CDCl₃): δ=1.31 (t,3H), 2.80 (q,2H), 7.23 (s,1H),8.88 (s,1H) ppm.

[0203] (iii) 4-(1-Bromoethyl)-6-chloropyrimidine

[0204] The product from Preparation 6(ii) (212 g) was dissolved indichloromethane (2.1 L). N-Bromosuccinimide (305.3 g) andazoisobutyronitrile (10.6 g) were added and the mixture was heated underreflux for 24 hours. Water (500 ml) was added and the heating underreflux was continued for a further 1 hour before cooling the mixture to20° C. The organic phase was separated, washed with aqueous sodiummetabisulphite solution (1 L) and then washed with water (1 L). Theorganic phase was dried with magnesium sulphate (20 g) and evaporatedunder reduced pressure to give the crude title compound as a dark oil(312 g, ca. 74% purity by ¹H-NMR calculation) that was used directly inExample 10.

[0205]¹H-NMR (300 MHz. CDCl₃): δ=2.03 (d,3H), 5.04 (q,1H), 7.51 (s,1H).8.95 (s,1H) ppm.

PREPARATION 7(2R,3S/2S,3R)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olR-(−)-10-camphorsulphonate

[0206]

[0207] 119:1(2R,3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-Chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olhydrochloride (40 g) was dissolved in methanol (360 ml). 10% w/wPalladium-on-carbon (50% w/w water content) (5.6 g) and ammonium formate(24 g) were added under an atmosphere of nitrogen. The reaction washeated under reflux for 2 hours and cooled to 25° C. The catalyst wasremoved by filtration and washed with methanol (120 ml). The filtratewas divided into two parts (2×ca. 245 ml).

[0208] One part was concentrated under reduced pressure and the residuedissolved in methylene chloride (95 ml) and water (95 ml) and stirredfor 15 minutes. The organic layer was separated, washed with water (2×60ml) and concentrated under reduced pressure to an oil. Isopropanol (100ml) was added and the mixture concentrated under reduced pressure.Isopropanol (90 ml) was added and the mixture heated to 55° C. to give asolution. A solution of R-(−)-10-camphorsulphonic acid (10.75 g) inisopropanol (21.5 ml) was added to this solution. The resulting slurrywas cooled to 25° C., granulated for 1 hour, cooled to 0° C. andgranulated for a further 2 hours. The product was isolated byfiltration, washed with cold isopropanol (2×20 ml) and dried underreduced pressure to provide the title compound (23.7 g). HPLC analysisusing the conditions set out in Example 1 showed the product to be puretitle compound.

PREPARATION 8(2R.3S/2S,3R)-2-(2,4-Difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

[0209]

[0210]16.36:1(2R,3S/2S,3R)-:(2R,3R/2S,3S)-3-(4-Chloro-5-fluoropyrimidin-6-yl-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olhydrochloride (1.7 kg, containing solvent: proportion of (2R,3S/2S,3R)enantiomeric pair calculated to be 1.08 kg) was added to methylenechloride (8.5 L) and water (8.5 L) with stirring. The mixture wasbasified to pH 11 with 40% aqueous sodium hydroxide solution and thelayers separated. The aqueous phase was extracted with methylenechloride (1.7 L). The combined organic extracts were washed with asolution of disodium ethylenediaminetetraacetic acid dihydrate (425 g)in water (8.5 L), and then water (2×5 L). The methylene chloridesolution was divided into two unequal parts. Both parts wereconcentrated under reduced pressure to afford oils (containing 198 g and980 g of the free bases, allowing for solvent, by ¹H-NMR calculation).HPLC analysis using the conditions set out in Example 1 showed the oilsto contain 76% and 69% by weight, respectively, of(2R,3S/2S,3R)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol.

[0211] The “980 g” sample was dissolved in methanol (10 L) and 10% w/wpalladium-on-carbon (50% w/w water content) (Johnson Matthey type 87 L)(69 g) and ammonium formate (322 g) added under an atmosphere ofnitrogen. The reaction was heated under reflux for 3 hours and cooled to40° C. The catalyst was removed by filtration and the filtrateconcentrated to an oil. Methylene chloride (5 L) and water (5 L) wereadded to the oil and the mixture stirred vigorously. The layers wereseparated and the aqueous layer was extracted with methylene chloride (1L). The combined organic phases were washed with water (2×3 L),concentrated under reduced pressure, isopropanol added and againconcentrated under reduced pressure. Isopropanol was added (3 L) and theslurry granulated at 0° C. for 1 hour. The product was collected byfiltration, washed with isopropanol and dried under reduced pressure at50° C. overnight to provide the title compound (547 g). HPLC analysisusing the conditions set out in Example 1 showed the product to be 97%pure title compound.

PREPARATION 9(2R,3S/2S,3R)-2-(2,4-Difluorophenyl)-3-(pyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol

[0212]

[0213] A mixture of(2R,3S/2S,3R)-:(2R,3R:2S,3S)-3-(4-chloropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol(the product of Example 10) (70 g), ammonium formate (24.1 g) and 10%w/w palladium-on-carbon (60% w/w water content) (Johnson Matthey type 87L) (4.7 g) in methanol (700 ml) was heated under reflux for 2 hoursunder an atmosphere of nitrogen. After cooling to 25° C., the reactionwas filtered and concentrated under reduced pressure. The residue wasdissolved in dichloromethane (500 ml) and washed with water (2×500 ml).The organic phase was dried with magnesium sulphate, concentrated underreduced pressure and the resulting gum was crystallised from isopropanol(250 ml) at −10° C. The product was collected by filtration to give thetitle compound (38.1 g) after drying at 50° C. under reduced pressure.

[0214]¹H-NMR (300 MHz, CDCl₃): δ=1.1 (d,3H), 3.65 (q,1H), 4.15 (d,1H),4.8 (d,1H), 6.55 (s,1H), 6.8 (m,2H), 7.4 (d,1H), 7.5 (m,1H), 7.6 (s,1H),7.9 (s,1(d,1H), 9.15 (s,1H) ppm.

1. A process for the preparation of a compound of the formula:

or an acid addition or base salt thereof, wherein R is phenyl optionallysubstituted by 1 to 3 substituents each independently selected from haloand trifluoromethyl; R¹ is C₁-C₆ alkyl; and “Het” is pyrimidinyloptionally substituted by 1 to 3 substituents each independentlyselected from C₁-C₄ alkyl, C₁-C₄ alkoxy, halo, oxo, benzyl andbenzyloxy, comprising reaction of a compound of the formula:

wherein R is as previously defined for a compound of the formula (I),with a compound of the formula:

wherein R¹ and “Het” are as previously defined for a compound of theformula (I) and X is chloro, bromo or iodo, in the presence of zinc,iodine and/or a Lewis acid and an aprotic organic solvent: said processbeing optionally followed by conversion of the compound of the formula(I) to an acid addition or base salt thereof.
 2. A process as claimed inclaim 1 wherein lead is also present.
 3. A process as claimed in claim 1or 2 wherein iodine is used.
 4. A process as claimed in claim 3 which iscarried out by mixing a solution or solutions of the compounds of theformulae (II) and (III) and iodine in an aprotic organic solvent with amixture of zinc, iodine, optionally lead, optionally a Lewis acid, andan aprotic organic solvent.
 5. A process as claimed in any precedingclaim wherein the Lewis acid, when used, is zinc chloride, zinc bromideor zinc iodide.
 6. A process as claimed in any preceding claim whereinthe aprotic organic solvent is tetrahydrofuran.
 7. A process as claimedin any preceding claim wherein an acid addition salt of the compound ofthe formula (I) is prepared.
 8. A process as claimed in claim 7 whereinthe acid addition salt is the hydrochloride, hydrobromide, hydroiodide,sulphate, nitrate, methanesulphonate, camphorsulphonate,R-(−)-10-camphorsulphonate, (+)-3-bromo-10-camphorsulphonate,(−)-3-bromo-8-camphorsulphonate, phosphate, para-toluenesulphonate orbenzenesulphonate salt, and preferably is the hydrochloride salt.
 9. Aprocess as claimed in any preceding claim wherein R is phenylsubstituted by 1 or 2 substituents each independently selected fromfluoro and chloro.
 10. A process as claimed in claim 9 wherein R isphenyl substituted by 1 or 2 fluoro substituents.
 11. A process asclaimed in claim 10 wherein R is 2,4-difluorophenyl.
 12. A process asclaimed in any preceding claim wherein R¹ is methyl.
 13. A process asclaimed in any preceding claim wherein “Het” is pyrimidinyl optionallysubstituted by 1 to 3 substituents each independently selected fromhalo, oxo and benzyl.
 14. A process as claimed in claim 13 wherein “Het”is pyrimidinyl optionally substituted by 1 to 3 substituents eachindependently selected from fluoro, chloro, oxo and benzyl.
 15. Aprocess as claimed in claim 14 wherein “Het” is pyrimidinyl substitutedby 1 to 3 substituents each independently selected from fluoro andchloro.
 16. A process as claimed in claim 14 wherein “Het” ispyrimidin-4-yl, 4-chloro-5-fluoropyrimidin-6-yl, 5-fluoropyrimidin-4-yl,2-chloro-5-fluoropyrimidin-6-yl, 2,4-dichloro-5-fluoropyrimidin-6-yl,4-chloropyrimidin-6-yl or 1-benzyl-5-fluoropyrimidin-6-on-4-yl.
 17. Aprocess as claimed in claim 16 wherein “Het” is4-chloro-5-fluoropyrimidin-6-yl.
 18. A process as claimed in anypreceding claim wherein X is bromo.
 19. A process for the preparation ofa compound of the formula:

or an acid addition salt thereof, wherein R and R¹ are as previouslydefined for a compound of the formula (I) in claim 1 and R² is H orfluoro, which comprises the steps of: (a) reaction of a compound of theformula:

wherein R is as defined for a compound of the formula (IV), with acompound of the formula:

wherein X is chloro, bromo or iodo, R¹ and R² are as previously definedfor a compound of the formula (IV) and either R³ and R⁴ are eachindependently selected from chloro and bromo or one of R³ and R⁴ ischloro or bromo and the other is H, in the presence of zinc, iodineand/or a Lewis acid and an aprotic organic solvent, to provide acompound of the formula:

wherein R, R¹, R², R³ and R⁴ are as previously defined for this step(a); (b) optionally converting the compound of the formula (IA) to anacid addition salt thereof; (c) reduction of the compound of the formula(IA) or an acid addition salt thereof to provide the compound of theformula (IV); and (d) optionally converting the compound of the formula(IV) to an acid addition salt thereof.
 20. A process as claimed in claim19 wherein lead is also present in step (a).
 21. A process as claimed inclaims 19 or 20 wherein in step (a) iodine is used.
 22. A process asclaimed in any one of claims 19 to 21 wherein the aprotic organicsolvent in step (a) is tetrahydrofuran.
 23. A process as claimed in anyone of claims 19 to 22 wherein the acid addition salt in step (b) is thehydrochloride, methanesulphonate or p-toluenesulphonate salt.
 24. Aprocess as claimed in any one of claims 19 to 23 wherein the reductionin step (c) is carried out by catalytic hydrogenation or by transferhydrogenation.
 25. A process as claimed in claim 24 wherein thereduction is carried out by transfer hydrogenation.
 26. A process asclaimed in claim 25 wherein the transfer hydrogenation is carried outusing palladium and ammonium formate.
 27. A process as claimed in anyone of claims 19 to 26 wherein the acid addition salt in step (d) is theS-(+)- or R-(−)-10-camphorsulphonate salt.
 28. A process as claimed inany one of claims 19 to 27 wherein R is 2,4-difluorophenyl.
 29. Aprocess as claimed in any one of claims 19 to 28 wherein R¹ is methyl.30. A process as claimed in any one of claims 19 to 29 wherein R² isfluoro.
 31. A process as claimed in any one of claims 19 to 30 wherein(i) R³ is chloro and R⁴ is H; (ii) R³ is H and R⁴ is chloro; or (iii) R³and R⁴ are both chloro.
 32. A process as claimed in claim 31 wherein R³is chloro and R⁴ is H.
 33. A process as claimed in any one of claims 19to 32 wherein X is bromo.
 34. A process as claimed in any one of claims19 to 27 wherein R is 2,4-difluorophenyl, R¹ is methyl, R² is fluoro, R³is chloro, R⁴ is H and X is bromo.
 35. A process as claimed in any oneof claims 19 to 27 wherein the compound of the formula (IA) is3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,3-(2-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,3-(2,4-dichloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,or an acid addition salt of any thereof.
 36. A process as claimed in anyone of claims 19 to 27 wherein the compound of the formula (IV) is2-(2,4-difluorophenyl)-3-(5-fluoropyrimidin-4-yl)-1-(1H-1,2,4-triazol-1-yl)butan-2-olor an acid addition salt thereof.
 37. A compound of the formula (I) asdefined in claim 1 which is (i)(2R,3S)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol;(ii) an acid addition salt of (2R,3S/2S,3R)- or(2R,3S)-3-(4-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-oland preferably the hydrochloride salt; (iii)3-(2,4-dichloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,or the (2R,3S/2S,3R)- or (2R,3S)-form thereof, or an acid addition saltof any thereof; (iv)3-(2-chloro-5-fluoropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,or the (2R,3S/2S,3R)- or (2R,3S)-form thereof, or an acid addition saltof any thereof; (v)3-(1-benzyl-5-fluoropyrimidin-6-on-4-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1-yl)butan-2-ol,or the (2R,3S/2S,3R)- or (2R,3S)-form thereof, or an acid addition saltof any thereof; or (vi)3-(4-chloropyrimidin-6-yl)-2-(2,4-difluorophenyl)-1-(1H-1,2,4-triazol-1yl)butan-2-ol,or the (2R,3S/2S,3R)- or (2R,3S)-form thereof, or an acid addition saltof any thereof.
 38. A compound of the formula (III) as defined in claim1 which is (i) 6-(1-bromoethyl)-2,4-dichloro-5-fluoropyrimidine; (ii)4-(1-bromoethyl)-6-chloropyrimidine; (iii)6-(1-bromoethyl)-4-chloro-5-fluoropyrimidine; (iv)1-benzyl-4-(1-bromoethyl)-5-fluoropyrimidin-6-one; (v)6-(1-bromoethyl)-2-chloro-5-fluoropyrimidine; or (vi)4-(1-bromoethyl)-5-fluoropyrimidine. 39.2-Chloro-6-ethyl-5-fluoro-4-hydroxypyrimidine, ammonium salt.